It has been reported that, of the hypertension patients in US, only 35% can appropriately control the blood pressure. One of the major causes of such poor achievements of the hypertension treatment is patients' disobedience (namely, non-compliance) to the instruction of the doctors. As a therapy capable of solving the problem of non-compliance, vaccine for hypertension is drawing attention (non-patent document 1).
Vaccine for hypertension is a therapeutic method for hypertension including administering an aggravation factor of hypertension, an epitope contained in the aggravation factor, or an expression vector encoding them to hypertension patients to induce an antibody to the aggravation factor in the body of the hypertension patients, thereby neutralizing the function of the aggravation factor and mitigating the symptoms of hypertension. Various factors including rennin, angiotensin II and AT-1 receptor are proposed as the target of vaccine (non-patent document 1).
However, the immune tolerance to factors such as renin, angiotensin II, AT-1 receptor and the like has generally been established since these factors are the patient's own component. Therefore, it is difficult to induce an antibody to the factor in the body of the patient even when these factors or partial peptides thereof are directly administered to the patient. As such, some technical idea is necessary to have the patient's immune system recognize these self-antigens, thereby inducing the production of the antibody thereto.
Hepatitis B virus core (HBc) antigen protein constitutes spherical core particles by self-assembly. The core particles have very high immunogenicity. When a fusion polypeptide obtained by inserting a desired epitope into a particular site of the HBc antigen protein, or connecting a desired epitope to the terminus of the HBc antigen protein is used, the epitope is presented on the surface of the particles formed by self-assembly. Using the fusion polypeptide, the inserted epitope is easily recognized by the immune system, and the production of the antibody that recognizes the epitope can be efficiently induced. Therefore, utilizing the HBc antigen protein as a platform of vaccine, attempts have been made to induce production of the antibody even though an antigen is difficult to be recognized by the immune system (non-patent document 2, non-patent document 3).
Patent document 1 discloses particles composed of a chimeric HBc antigen protein containing a foreign amino acid sequence having an epitope, wherein the foreign amino acid sequence is inserted between the amino acid residues 80-81 of the HBc antigen.
Patent document 2 and non-patent document 4 disclose complexes containing partial peptide of angiotensin II, spacer and virus-like particles (VLP), wherein the partial peptide of angiotensin II is connected to VLP via the spacer. It is described that the complex is useful as a vaccine for hypertension.
Patent document 3 discloses an immunogenic polypeptide obtained by inserting a cholesteryl ester transfer protein (CETP) immunogen to a particular region of Hepatitis B core protein.
Non-patent document 5 discloses that intramuscular immunization with a DNA vaccine encoding an epitope of cholesteryl ester transfer protein (CETP) consisting of 26 amino acids, which is displayed by Hepatitis B virus core (HBc) antigen protein, and containing CpG DNA inhibits arteriosclerosis in a rabbit arteriosclerosis model. This DNA vaccine is designed to permit insertion of CETP epitope between the amino acid residues 80-81 of the HBc antigen protein.
Non-patent document 6 discloses that the position of heterologous epitopes inserted in Hepatitis B virus core (HBc) antigen protein determines their immunogenicity. It discloses that insertion of an epitope between the amino acid residues 75-81 of the Hepatitis B virus core (HBc) antigen protein results in an increased antibody titer to the inserted epitope and decreased antibody titer to HBc.
Non-patent document 7 discloses that hybrid HBcAb-CS particles designed to permit insertion of malaria CS protein repeat epitope between the amino acid residues 75-81 of Hepatitis B virus core (HBc) antigen protein prevented malaria infection in mouse.
To potentiate the immune effect, it has been proposed to add an immunostimulatory sequence (ISS) as an adjuvant to a vaccine, or insert ISS into an expression vector of the active ingredient (non-patent document 8).
However, the effectiveness of the vaccine for lifestyle-related diseases such as hypertension and the like is not sufficiently satisfactory.